The potential utility of evoked potentials in the treatment of mental illnesses

The “Decade of the Br ain” r eferr ed to the 1990s, as the emergence of various brain imaging techniques allo w ed the analysis of both normal and pathological behaviors with specific patterns of distributed neural activity (Insel and Quirion, 2005 ). Among these tec hniques, electr oencephalogr a phy (EEG) indexed sponta-neous brain electrical activity, and included e v ent-r elated potentials (ERPs), referring to epochs of EEG activity that are time-locked to the processing of stimuli (Rugg and Coles, 1995 ). Once mental diseases were also envisaged as resulting from brain alterations (Price et al. , 2000 ), a neur ocognitiv e a ppr oac h emer ged, pr omoting that: (i) significant cognitive disturbances are observed in psychiatric diseases (Green, 2006 ); (ii) these cognitive disturbances, indexed by dysfunctional neural networks , ma y trigger/subtend the onset and/or maintenance of clinical symptoms, thereby defining v alid ther a peutic tar gets (Ver dejo-Gar cia et al. , 2023 ); and (iii) re-habilitating these cognitive functions (through neuropsychological training programs and/or neuromodulation tools) disclosed encour a ging r esults

The "Decade of the Br ain" r eferr ed to the 1990s, as the emergence of various brain imaging techniques allo w ed the analysis of both normal and pathological behaviors with specific patterns of distributed neural activity (Insel and Quirion, 2005 ).Among these tec hniques, electr oencephalogr a phy (EEG) indexed spontaneous brain electrical activity, and included e v ent-r elated potentials (ERPs), referring to epochs of EEG activity that are time-locked to the processing of stimuli (Rugg and Coles, 1995 ).Once mental diseases were also envisaged as resulting from brain alterations (Price et al., 2000 ), a neur ocognitiv e a ppr oac h emer ged, pr omoting that: (i) significant cognitive disturbances are observed in psychiatric diseases (Green, 2006 ); (ii) these cognitive disturbances, indexed by dysfunctional neural networks , ma y trigger/subtend the onset and/or maintenance of clinical symptoms, thereby defining v alid ther a peutic tar gets (Ver dejo-Gar cia et al., 2023 ); and (iii) rehabilitating these cognitive functions (through neuropsychological training programs and/or neuromodulation tools) disclosed encour a ging r esults by pr omoting r eduction of clinical symptoms as well as enhancement of patients' quality of life (Lesniak et al., 2014 ).In this view, ERPs, considered a useful tool to probe the information pr ocessing str eam in the br ain, can help pinpoint the specific neur ocognitiv e functions that should be tar geted in eac h patient through specific and indi vidualized cogniti v e r emediation pr ocedur es (Campanella, 2016 ).Ob viousl y, e v en if we choose to focus this perspective paper on cognitive ERPs, several other electrophysiological tools (such as transcranial magnetic stimulation or neural oscillations) have proved to be useful for studying neurophysiological biomarkers of psychiatric disorders (Cao et al., 2021 ;Ferr ar elli and Phillips, 2021 ).
Focusing on cognitive ERPs was triggered by the current idea that it is important to e v aluate whic h cognitiv e dysfunction(s) may subtend the onset and/or maintenance of a clinical symptom to be able to rehabilitate (them) and to reduce the se v erity of this clinical symptom.Indeed, empirical evidence indicates that (i) some cognitive ERP markers can predict the clinical trajectory of psychiatric patients (Dousset et al., 2022 ;Kim et al., 2023 ); and (ii) cognitive training programs combined with neuromodulation tools can induce specific neur al c hanges (Campanella et al., 2017 ;Sc hr oder et al., 2020 ;Dousset et al., 2021 ) and promote clinical symptom reduction (Monnart et al., 2019 ;Dubuson et al., 2021 ).The most interesting part of such findings was to suggest that cognitiv e disturbances ar e closel y linked to the onset and maintenance of clinical symptoms (e.g.altered inhibitory skill can favor nega-ti ve intrusi ve thoughts in de pressi ve disorders as well as a r ela pse in alcohol dependence; Monnart et al., 2016 ;Petit et al., 2014 ), or that v arious ERP par ameters , i.e .the oddball P300 and the No-Go P300 components (ERP waveforms classically recorded thanks to the oddball and the Go/No-go tasks), could predict abstinence vs. r ela pse at 3 months in r ecentl y detoxified alcoholic patients (Campanella et al., 2020 ).
Indexing cognitive alterations could of course be done through neur opsyc hological testing, but this is too time consuming in psyc hiatric settings.Cognitiv e ERPs may then be used to quic kl y tar get main cognitiv e r estrictions.Ho w e v er, despite being non-inv asiv e, globall y av ailable, and cost-effectiv e, and showing decades of r esearc h with r ecent encour a ging r esults, the clinical utility of ERPs in psychiatry is still poor.A theor eticall y gr ounded fr ame work to concr etel y a ppl y ERPs in psyc hiatric car e units has been proposed (Campanella, 2021 ).Currently, clinical symptoms are at the first plan to drive psychiatric evaluations, and the clinical trajectory is monitored by clinical interviews.Ho w ever, reaching a diagnostic does not usually include the use of biomarkers (Casey et al., 2013 ).Once the idea that disturbed brain networks also subtend psychiatric diseases was admitted, a further assumption was to acknowledge that these neural alterations should be reflected in long-lasting neural modifications to trigger enduring real-world behavioral changes (Vinogradov et al., 2012 ).
Ther efor e, we pr omoted test-r etest ERP sessions at the individual le v el to favor "individualized" or "personalized" medicine (Campanella et al., 2019 ).Indeed, ERP markers may help (i) to monitor the spontaneous and/or tr eatment-r elated e volution of the specific neur ocognitiv e pr ocesses that trigger ed the onset and persistence of all clinical symptoms observed in singular patients; and (ii) to e v aluate whether these brain modifications triggered by the tr eatment can pr edict the clinical e volution of the patient (Fig. 1 ).Two recent ERP case reports sho w ed, for instance, a perfect congruenc y betw een the clinical and the neur ophysiological e volution (indexed through the P300 component) of a psychotic patient (Kajosch et al., 2020 ), and that cognitive ERPs may be used as rele v ant indicators of cognitive vulnerabilities in individual patients (Ingels et al., 2022 ).
To r eac h this aim, thr ee main dir ections hav e been pr oposed (Campanella, 2021 ): (i) the definition of clear and applicable multisite guidelines to validate an unambiguous set of normative data; (ii) the promotion of a multi-component ERP approach; and (iii) the de v elopment of ERP serial r ecordings.First, at the methodological le v el, the worldwide curr ent ERP liter atur e is r epr esented by a huge number of ERP studies reporting se v er al conflicting r esults, mainl y due to technical variations (Hajcak et al., 2019 ).Such variability in reported data has of course generated a lot of scepticism among clinicians as it raises questions r egarding r eliability.At the clinical le v el, tec hnical guidelines already exist for some main ERPs (e.g. the P300, Duncan et al., 2009 ); ho w e v er, their use is still by no means widespread throughout the world, and this could sometimes lead to some misunderstanding of the data (Campanella and Colin, 2014 ).De v eloping suc h normativ e tec hnical guides adopted by the whole field would clearly help with clinical implementation.In this w ay, w e w ould guarantee access to normative data recorded from large samples using similar pr ocedur es so as to index the pr ogr ession of patients' scor es as a function of the treatment, but also ensuring that the impact of some potential confounding variables (sex, age, drug, or comorbidity for instance) was controlled for.
Second, a main adv anta ge of ERPs is to present a high degree of sensitivity combined with some pr edictiv e po w er.Ho w e v er, it suffers from poor specificity (Pogarell, 2007 ).Accordingly, it could be argued that a "multivariate endophenotype," mainly based on a weighted mixture of various ERP components (P50, P300, and mismatch negativity), may help to furnish a reliable diagnostic more accur atel y than an y single component (Price et al., 2006 ).Further ERP recordings should then use a m ulti-component a ppr oac h to potentiall y incr ease the sensitivity and/or specificity of ERP studies by decreasing the impact of group heterogeneity.This could also allow a better specification of the individual cognitive process(es) that should be reeducated in a singular patient.
Third, ERPs r epr esented a well-suited tool for using serial recor dings in follo w-up studies to index neural modifications induced by a specific tr eatment (Pogar ell et al., 2007 ).Indeed, if there ar e differ ences in wav esha pe, size, and timing of ERPs between individuals , ERPs ha ve disclosed high stability within an individual due to a high internal consistency and a high test-retest reliability (Kappenman et al., 2017 ).Consequently, as ERPs can be r ecorded man y times fr om the same individual with high reliability, session-r elated c hanges r eported in br ain activity should r esult from treatment intervention or disease evolution in a singular patient (Kappenman and Luck, 2016 ).Overall, by fostering a multi-component follow-up approach, ERPs may be used to monitor and/or predict specific modifications in brain function in response to ther a py (e.g.psyc ho-social support, medication) as well as to index specific remaining cognitive alterations.In this way, clinicians may promote adapted individual interventions that will be tailored to the specific needs of an individual patient, thus providing a "personalized" medicine.

Figure 1 :
Figure 1: Illustration of ERP screening on an individual patient through test-retest sessions to orient neurocognitive rehabilitation.